1. Field of Technology
The present invention relates to a treatment for hydrocephalus. More particularly, the present invention relates to the intraventricular administration of a growth factor to treat hydrocephalus.
2. Description of Related Art
Hydrocephalus sometimes follows meningitis and intracranial hemorrhage, especially after bacterial meningitis or subarachnoid hemorrhage (SAH) (Di Rocco, C., at al, J. Neurol Sci, 1977. 33(3): p. 437-452; Yasargil, M. G., et al., J Neurosurg, 1973. 39(4): p. 474-479; Almuneef, M., et al., J Infect, 1998. 36(2): p. 157-160; Dacud, A. S., et al., J Trop Pediatr., 1998. 44(3): p. 167-169; Gomes, I., et al., Arq Neuropsiquiatr, 1996. 54(3): p. 407-411; Grimwood, K., et al., Pediatrics, 1995. 95(5): p. 646-656). Patients with hydrocephalus present elevated intracranial pressure signs such as headache and vomiting in the acute phase, and show character changes in behavior and decline in school performance in the chronic phase (Youmans, J. R., ed. Neurological Surgery, fourth edition ed. C. Saint Rose. Vol. 2. 1996, W.B. Saunders Company: Philadelphia, p. 890-926). Elderly patients with hydrocephalus present memory disturbance, gait disturbance and urinary incontinence without headache; this Is widely known as “normal pressure hydrocephalus” (Adams, R. D., et al., The New England Journal Of Medicine, 1965. 273(1965): p. 117-126; Graff-Radford, N. R., et al., Arch Neurol, 1989. 46(7): p. 744-752; Pfister, H. W., Feiden, W., and Einhaupl, K. M., Arch Neurol, 1993. 50(6): p. 575-581). Reversible dementia is one of the best known symptoms of normal pressure hydrocephalus in humans (Youmans, J. R., ed. Neurological Surgery, fourth edition ed. C. Saint Rose. Vol. 2. 1996, W.B. Saunders Company: Philadelphia, p. 890-926).
In communicating hydrocephalus, communication is established between the ventricles and a drainage cavity such as the peritoneum (Youmans, J. R., ed. Neurological Surgery, fourth edition ed. C. Saint Rose. Vol. 2. 1996, W.B. Saunders Company: Philadelphia, p. 890-926), in contrast to obstructive hydrocephalus, which involves compression or obliteration of the route of cerebrospinal fluid (CSF) by a brain tumor or membrane. The causes of communicating hydrocephalus have not yet been clarified. Histological evidence of fibrosis of arachnoid villi and subarachnoid space has been found in many autopsy studies (Lobato, R. D., et al., J. Neurosurg, 1981. 55(5): p. 786-793; Torvik, A., Bhatia, R., and Murthy, V. S., Acto Neurochir (Wien), 1978. 41(1-3): p. 137-146; Akai, K., et al., Acta Pathol Jpn, 1987. 37(1): p. 97-110). Some autopsy reports suggest that a possible cause is proliferation of arachnoid cap cells of arachnoid granules, but there is no conclusive evidence that this is specific to hydrocephalic patients (Massicotte, E. M. and Del Bigio, M. R., J Neurosurg, 1999. 91(1): p. 80-84; Motohashi, O., et al., Acta Neurochir (Wien), 1995. 136(1-2): p. 88-91). Therefore, it is reasonable to speculate that fibrosis of the subarachnoid space and arachnoid villi causes a mild pressure gradient across the CSF flow route, and that this is a major factor in development of hydrocephalus. Currently, shunting is the only definitive therapy for communicating hydrocephalus. However, there are many potential complications for people who undergo shunting surgery (Kang, J. K. and Lee, I. W., Child's Nervous System, 1999. 15(11-12): p. 711-717). The parents of patients shunted in infancy should be made aware of the possible problems with shunting. Even with patients who have been stable for a long period, significant clinical problems may arise during adulthood. These problems require replacement of the shunt system Joon-Ki and I. W. Lee, Child's Nervous System, 1999. 15: p. 711-717). It is essential for neurosurgeons to follow shunted patients for a long time (Sgouros, S., et al., Pediatr Neurosurg, 1995. 23(3): p. 127-132), and the social cost of maintaining such patients in good condition can be considerable (Del Bigio, M. R., Can J Neurol Sci, 1998. 25(2): p. 123-126).
Hepatocyte growth factor (HGF) was originally identified and cloned as a potent mitogen for mature hepatocytes (Nakamura, T. et al., Nature, 1989. 342(6248): p. 440-443; Miyazawa, K. et al., J. Biol Chem, 1993. 268(14): p. 10024-10028). It has a potent ability to reduce fibrosis in many organs, and it is expected to become a therapeutic material for various fibrotic diseases, including pulmonary fibrosis, liver cirrhosis and acute renal failure (Dohi, M. et al., Am J Respir Crit Care Med, 2000. 162(6): p. 2302-2307; Matsuda, Y. et al., J Biochem (Tokyo), 1995. 118(3): p. 643-649; Fujimoto, J., J Gastroenterol Hepatol, 2000. 15 Suppl: p. D33-D36; Vargas, G. A., Hoeflich, A., and Jehle, P. M., Kidney Int, 2000. 57(4): p. 1426-1436). HGF is a multi-potent growth factor that has mitogenic, motogenic and morphogenic effects on various epithelial cells and is produced by mesenchyme. It acts upon epithelial tissues in liver, kidney and lung, and counteracts the fibrosis-inducing effect of TGF-β1 (Rosen, E. M., Nigam, S. K. and Goldberg, I. D., J Cell Biol, 1994. 127(6 Pt 2): p. 1783-1787; Brinkmann, V. et al., J Cell Biol, 1995. 131(6 Pt 1): p. 1573-1586; Ohmichi, H. et al., Development, 1998. 125(7): p. 1315-1324; Matsumoto, K., Mizuno, S. and Nakamura, T., Curr Opin Nephrol Hypertens, 2000. 9(4): p. 395-402). Neutralization of HGF by antibody leads to acceleration of renal failure/fibrosis, and administration of exogenous HGF leads to marked attenuation of renal failure/fibrosis (Matsumoto, K., Mizuno, S. and Nakamura, T., Curr Opin Nephrol Hypertens, 2000. 9(4): p. 395-402).
The present invention is directed to the aforementioned problems. An object of the present invention is to provide an improved treatment for hydrocephalus using hepatocyte growth factor (HGF). To this end, a model of hydrocephalus in mice by administering human recombinant (hr) transforming growth factor β1 (TGF-β1) (Tada, T., Kanaji, M. and Kobayashi, S. J Neuroimmunol, 1994. 50(2): p. 153-158) has been tested; such hydrocephalic mice present with clear disturbance of spatial learning ability in a water maze test. In the present hydrocephalus model, learning disturbance is reversible, which is very unique for such models, and is similar to human normal pressure hydrocephalus. The present invention therefore presents an alternative to shunting as a therapy for hydrocephalus.